Note: Descriptions are shown in the official language in which they were submitted.
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Administration of Cisplatiu by Inhalation
Related Applications
This application claims the benefit of priority to United States Provisional
Application serial number 60/554,262, filed March 18, 2004, and United States
Provisional
Application serial number 60/573,521, filed May 21, 2004; the entirety of
which are hereby
incorporated by reference.
Background of the Invention
The present invention relates to a method for treating cancer by delivering a
therapeutically effective amount of a lipid composition containing a cytotoxic
agent (e.g.,
cisplatin) to a patient's respiratory tract. The method allows clinicians to
administer
treatment cycles more frequently without the attendant side effects (e.g.,
nephrotoxicity,
bone marrow toxicity) common to systemic administration of many cancer
cytotoxic agents
(e.g., cisplatin).
Bronchoalveolar Carcinoma (BAC) or alveolar cell carcinoma is a form of
adenocarcinoma, a cell-type of non-small cell carcinoma of the lung which can
be found
throughout the respiratory tract. BAC represents approximately 10 to 25% of
the
adenocarcinoma of lung cases or 2-6% of all lung cancers and sometimes has a
distinct
presentation and biologic behavior. BAC is more common in women and in
patients who
do not smoke cigarettes than other histologic types of lung cancer.
BAC may present as a solitary peripheral nodule, a multifocal lesion, or a
rapidly
progressive form that appears as a diffuse infiltrate on chest radiograph. The
cells secrete
mucin and surfactant apoprotein which can lead to bronchorrhea, an excessive
discharge of
mucus from the air passages of the lungs. Bronchoalveolar cancer may present
as a more
diffuse lesion than other types of cancer. When it is discovered as a single
mass on a
patient's x-ray, this type of lung cancer has an excellent prognosis. Five
year survival after
surgery is in the 75-90 percent range. If, however, it is found in its diffuse
form (meaning it
has spread beyond a single mass), the prognosis is quite poor.
The management and prognosis are essentially the same as other types of non-
small
cell lung cancer. Surgery is the preferred treatment if the tumor can be
resected. Radiation
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therapy and chemotherapy may be used in non-operable cases. Trials are
underway to
investigate treatments specific for bronchoalveolar carcinoma.
Carcinomatosis with lymphangitic spread, or Lymphangitis carcinomatosis (LC)
refers to the diffuse infiltration and obstruction of pulmonary parenchyma)
lymphatic
channels by tumor. Various neoplasms can cause lymphangitic carcinomatosis,
but 80%
are adenocarcinomas. The most frequent primary sites are the breast, lungs,
colon, and
stomach. Other sources include the pancreas, thyroid, cervix, prostate,
larynx, and
metastatic adenocarcinoma from an unknown primary.
LC occurs as a result of initial hematogenous spread of tumor to the lungs,
with
subsequent malignant invasion through the vessel wall into the pulmonary
interstitium and
lymphatics. The tumor then proliferates and spreads easily through these low
resistance
channels. Less commonly, direct infiltration occurs from contiguous
mediastinal or hilar
lymphadenopathy or from an adjacent primary bronchogenic carcinoma.
Histopathologically, interstitial edema, interstitial fibrosis (secondary to a
desmoplastic
reaction as a result of tumor extension into adjacent pulmonary parenchyma),
and tumor
cells all can be seen. Metastatic adenocarcinoma accounts for 80% of cases.
Most patients
are middle-aged adults.
In the United States, LC represents 7% of all pulmonary metastases. Prevalence
in
postmortem studies is significantly higher than the incidence of
radiologically detectable
disease. Microscopic interstitial tumor invasion is seen in 56% of patients
with pulmonary
metastases. Prognosis for patients with LC is poor. Most patients survive only
weeks or
months.
Typically, chemotherapeutic treatment of lung cancers includes systemic
administration of chemotherapeutic agents, e.g., cytotoxic agents, to the
patients. Often
such administration, e.g., intravenous administration, is associated with
several adverse side
effects including nephrotoxicity and bone marrow toxicity. For instance,
systemic
administration of cisplatin (cis-diamine-dichloroplatinum (II)) one of the
more effective
anti-tumor agents used in the systemic treatment of lung cancers, is often
burdened by
symptoms such as nephrotoxicity in the patient. The nephrotoxicity limits the
frequency in
which clinicians can administer cisplatin to the patient. In fact, successive
treatment cycles
of cisplatin typically require three weeks or more between treatment cycles to
prevent blood
levels of cisplatin from reaching those correlated with nephrotoxicity. Since
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chemotherapeutic regimens typically require five or more treatment cycles, the
delay
between treatment cycles lengthens the time needed for the overall
chemotherapeutic
regimen. The prolonged time periods for systemic administration of cisplatin
lead to
increased patient discomfort and inconvenience, and may lead to decreased
patient
compliance.
Accordingly, new methods for treating patients suffering from lung cancer by
inhalation administration of cisplatin that allow significant local
concentrations of drug to
be attained by shortening of the time periods needed between treatment cycles
are desirable.
Such methods preferably also overcome the rapid clearance of cisplatin from
the lung that
typically plague inhalation administration of therapeutic agents.
Summary of tl:e Invention
In one aspect, the present invention features a method for treating a patient
having
cancer,~comprising administering a lipid composition comprising cisplatin to
the patient's
respiratory tract over the course of at least 2 treatment cycles, wherein: at
least about 15
mg/mz of cisplatin is administered in each treatment cycle; and there is no
more than 2
weeks between treatment cycles.
In a preferred embodiment, there is no more than 1 week between treatment
cycles.
In another preferred embodiment, the method comprises at least 3 treatment
cycles. In
another preferred embodiment, the method includes at least 4 treatment cycles,
and more
preferably, at least 5 treatment cycles.
In another preferred embodiment, the cisplatin to lipid ratio of the lipid
composition
is from about 1:50 to about 1:5 by weight. In a further embodiment, the
cisplatin to lipid
ratio of the lipid composition is from about 1:50 to about 1:10 by weight. In
a further
embodiment, the cisplatin to lipid ratio of the lipid composition is from
about 1:25 to about
1:15 by weight.
In another preferred embodiment, the lipid composition comprises a lipid
selected
from the group consisting of egg phosphatidylcholine (EPC), egg
phosphatidylglycerol
(EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg
phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy
phosphatidylcholine
(SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy
phosphatidylinositol (SPI), soy phospatidylethanolamine (SPE), soy phosphatic
acid (SPA),
hydrogenated egg phosphatidylcholine (HEPC), hydrogenated egg
phosphatidylglycerol
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(HEPG), hydrogenated egg phosphatidylinositol (HEPI), hydrogenated egg
phosphatidylserine (HEPS), hydrogenated egg phosphatidylethanolamine (HEPE),
hydrogenated egg phosphatidic acid (HEPA), hydrogenated Soya
phosphatidylcholine
(HSPC), hydrogenated soy phosphatidylglycerol (HSPG), hydrogenated soy
phosphatidylserine (HSPS), hydrogenated soy phosphatidylinositol (HSPI),
hydrogenated
soy phospatidylethanolamine (HSPE), hydrogenated soy phosphatic acid (HSPA),
dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidycholine (DMPC),
dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol
(DPPG),
distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG),
dioleylphosphatidyl-ethanolarnine (DOPE), palmitoylstearoylphosphatidyl-
choline (PSPC),
palmitoylstearolphosphatidylglycerol (PSPG), mono-oleoyl-
phosphatidylethanolamine
(MOPE), cholesterol, cholesterol hemi-succinate, cholesterol hydrogen sulfate,
cholesterol
sulfate, ergosterol, ergosterol hemi-succinate, ergosterol hydrogen sulfate,
ergosterol
sulfate, lanosterol, lanosterol hemi-succinate, lanosterol hydrogen sulfate,
lanosterol sulfate,
and mixtures thereof. In a further embodiment, the lipid composition comprises
DPPC. In
a further embodiment, the lipid composition comprises cholesterol. In still a
further
embodiment, the lipid component of the lipid composition comprises from about
50 to
about GS mol% of DPPC and about 35 to about 50 mol% cholesterol.
In another preferred embodiment, the lipid composition further comprises an
aqueous component. In a further embodiment, there is at least 80% by weight of
the
aqueous component in the lipid composition.
In another preferred embodiment, the lipid composition is administered as an
aerosol. In another preferred embodiment, the lipid composition is
administered with a
nebulizer at a flow rate of at least about 0.15 mL/min.
In another preferred embodiment, the lipid composition comprises one or more
liposomes.
In another preferred embodiment, the cancer is a lung cancer. In a further
embodiment, the lung cancer is selected from the group consisting of
bronchoalveolar
carcinoma and carcinomatosis with lymphangitic spread. In a further
embodiment, the lung
cancer is bronchoalveolar carcinoma.
In another aspect, the present invention features a method for treating a
patient
having bronchoalveolar carcinoma, comprising administering a lipid composition
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comprising cisplatin to the patient's respiratory tract over the course of at
least 5 treatment
cycles, wherein at least about 15 mg/m2 of cisplatin is administered in each
treatment cycle;
there is no more than 2 weeks between treatment cycles; the lipid composition
comprises
from about 50 to about 65 mol% of DPPC and about 35 to about 50 mol%
cholesterol; and
the cisplatin to lipid ratio is from about 1:25 to about 1:15 by weight.
In a preferred embodiment, the lipid composition further comprises at least
80% by
weight of aqueous component and the lipid composition is administered with a
nebulizer.
In a preferred embodiment, the lipid composition is administered with a
nebulizer at
a flow rate of at least about 0.15 mL/min.
These embodiments of the present invention, other embodiments, and their
features
and characteristics, will be apparent from the description and claims that
follow.
Detailed Description of the Invention
Definitions
For convenience, before further description of the present invention, certain
terms
employed in the specification, examples and appended claims are collected
here. These
definitions should be read in light of the remainder of the disclosure and
understood as by a
person of skill in the art. Unless defined otherwise, all technical and
scientific terms used
herein have the same meaning as commonly understood by a person of ordinary
skill in the
art.
An "active platinum" compound is a compound containing coordinated platinum
and having antineoplastic activity. Active platinum compounds include, for
example,
cisplatin, carboplatin, and DACH-platinum compounds such as oxaplatin.
A "patient," "subject" or "host" to be treated by the subject method may mean
either
a human or non-human animal.
The term "therapeutic effect" is art-recognized and refers to a local or
systemic
effect in animals, particularly mammals, and more particularly humans caused
by a
pharmacologically active substance. The phrase "therapeutically-effective
amount" means
that amount of a substance that produces some desired local or systemic effect
at a
reasonable benefit/risk ratio applicable to any treatment. The therapeutically
effective
amount of a substance will vary depending upon the subject and disease
condition being
treated, the weight and age of the subject, the severity of the disease
condition, the manner
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of administration and the like, which can readily be determined by one of
ordinary skill in
the art.
The term "treating" is art-recognized and refers to curing as well as
ameliorating at
least one symptom of a condition or disease or preventing the occurrence of a
condition or
disease.
"Treatment cycle" means the time period in which a given dose of cisplatin is
to be
administered to a patient. Treatment cycles may encompass one or more sessions
where the
patient is actively being administered the liposomal composition containing
cisplatin. Such
sessions may be administered over the course of four days or less, but more
preferably is
administered over one or two days.
General
Provided is a method for treating lung cancer by delivering a therapeutically
effective amount of a lipid composition containing cisplatin to a patient's
respiratory tract.
The method allows more intensive chemotherapeutic treatment of patients. In
particular,
with the methods of the invention clinicians may safely administer treatment
cycles with
cisplatin to patients more frequently. Consequently, less time is needed to
complete the
entire therapeutic regimen.
The method includes administering a lipid composition containing cisplatin to
the
patient's respiratory tract over the course of at least two treatment cycles.
During each
treatment cycle, at least about 1 S mg/m2 of cisplatin is administered to the
patient's
respiratory tract, and the time period between treatment cycles is no more
than two weeks.
As used herein the time period between the treatment cycles refers to the time
period
between initiation of each consecutive treatment cycle. The lipid composition
administered
is a liposomal/lipid complex composition containing cisplatin which may be,
for example,
combined with an aqueous component, e.g., saline, and administered as an
aerosol.
In general, the doses of cisplatin will be chosen by a physician based on the
age,
physical condition, weight and other factors known in the medical arts. In
each treatment
cycle preferred dosages are between approximately 15 mg/mz and approximately
60 mg/mz.
Generally there is no more than two weeks between treatment cycles, and
preferably, there
is no more than one week between treatment cycles.
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The method provides for a more intensive chemotherapeutic regimen for lung
cancer treatment due to the localized delivery of cisplatin to the respiratory
tract. Clinicians
may administer more drug to lung cancer patients with greater frequency of
treatment
cycles because the method minimizes systemic exposure of non-cancerous cells
in the body
to the toxic effects of cisplatin. The patient's propensity for
nephrotoxicity, which typically
limits the frequency of treatment cycles for systemically administered
cisplatin, is
diminished.
The method also overcomes the drawbacks generally associated with inhalation
administration of drugs due to the lipid composition. The lipid composition
(particularly
liposome-based compositions) serves to protect the cisplatin as it is
delivered to its target
site, and protects non-cancerous tissue from being exposed to the cytotoxic
effects of the
drug. In addition, the lipid composition facilitates adherence of the
composition to the
lungs, and slows the release of the drug, and thereby diminishes the rapid
clearance
typically associated with inhalational administration. Moreover, the
compositions are
sufficiently stable in the lungs to allow the formulation to remain effective
for a
therapeutically useful time period.
The method includes a lipid composition that has a very high cisplatin to
lipid ratio.
The bioactive agent to lipid ratio seen in the present invention is between
about 1:5 by
weight and about 1:50 by weight. More preferably, the bioactive agent to lipid
ratio seen is
between about 1:10 by weight and about 1:30 by weight. Most preferably, the
bioactive
agent to lipid ratio seen is between about 1:15 by weight and about 1:25 by
weight. When
formulated with an aqueous component for administration with a nebulizer, the
cisplatin
may be present in the final formulation at from about 0.5 mg/mL to about 1.7
mg/mL, and
is preferably present at from about 0.8 to about 1.3 mg/mL.
In addition to the lipid component, cisplatin, and optional aqueous component,
the
lipid composition may also contain commonly used pharmaceutically acceptable
excipients
(including solvents, salts and buffers), preservatives and surfactants.
The lipid compositions can include liposomes, lipid complexes, lipid
clathrates and
proliposomes, i.e., compositions which can form liposomes in vitro or in vivo
when
contacted with water. Compositions are preferably adopted for use by
inhalation, and more
preferably for use in an inhalation delivery device for the composition's
administration.
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The inhalation system can be used for the treatment of lung cancers in both
man and
animal.
Methods of Preparing the Lipid Compositions
The lipid composition is preferably formed as described in co-pending United
States
Patent Application Serial No. 10/634,144, filed August 4, 2003, which is
hereby
incorporated by reference in its entirety. Briefly, the lipid complex can be
formed by
mixing cisplatin with an appropriate lipid dissolved or suspended in a solvent
(e.g., ethanol)
and subjecting the mixture to one or more cycles have two separate
temperatures. The
process is believed to be in the form of an active platinum compound
aggregate.
In aqueous solution, cisplatin forms large crystalline aggregates with a
crystal
diameter of greater than a few microns. In the presence of an amphipathic
matrix system,
such as a lipid bilayer, cisplatin complexes with the lipid. For example, the
complexes may
be formed in the hydrocarbon core region of a lipid bilayer. During the
warming cycle of
the process, it is believed that cisplatin is returned to solution at a
greater rate in aqueous
regions of the process mixture than in the bilayers. As a result of applying
more than one
cool/warm cycle, cisplatin accumulates further in the lipid bilayers. Without
limiting the
invention to the proposed theory, experimentation indicates that the cisplatin
complexes
cause the immediate surroundings of the interfacial bilayer region to be more
hydrophobic
and compact. This results in a high level of entrapment of active platinum
compound as
cooling and warming cycles are repeated.
The formulation has a markedly high entrapment percentage of cisplatin. The
entrapment has been shown, in some cases, to reach upto about 20, 30, 40, 50,
60, 70, 80, or
about 90%. This amount is far higher than the most efficient entrapment
expected from a
conventional aqueous entrapment which is approximately 2-10% entrapment.
The process includes combining cisplatin with a hydrophobic matrix carrying
system (lipid/solvent mixture) and cycling the solution between a warmer and a
cooler
temperature. Preferably, the cycling is performed more than one time. More
preferably,
the step is performed two or more times, or three or more times. The cooler
temperature
portion of cycle can, for example, use a temperature from about -25 °C
and about 25 °C.
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More preferably, the step uses a temperature from about -5 and about 5
°C or between about
1 and about 5 °C. For manufacturing convenience, and to be sure the
desired temperature is
established, the cooler and warmer steps can be maintained for a period of
time, such as
approximately from about 5 to about 300 minutes or about 30 to about 60
minutes. The
step of warming includes warming the reaction vessel to from about 4 and about
70 °C.
More preferably, the step of warming comprises heating the reaction vessel to
from about
45 to about 55 °C. The above temperature ranges are particularly
preferred for use with
lipid compositions containing predominantly dipalmitoylphosphatidycholine
(DPPC) and
cholesterol.
Another way to consider the temperature cycling is in terms of the temperature
differential between the warmer and the cooler steps of the cycle. This
temperature
differential can be, for example, about 25 °C or more, such as a
differential from about 25
to about 70 °C, preferably a differential from about 40 to about 55
°C. The temperatures of
the cooler and higher temperature steps are selected on the basis of
increasing entrapment
of active platinum compound. Without being limited to theory, it is believed
that it is
useful to select an upper temperature effective to substantially increase the
solubility of
active platinum compound in the processed mixture. Preferably, the warming
step
temperature is about 50 °C or higher. The temperatures can also be
selected to be below
and above the transition temperature for a lipid in the lipid composition.
The temperatures appropriate for the method describe above may, in some cases,
vary with the lipid composition used in the method, as can be determined by
ordinary
experimentation.
Experimental results strongly indicate that encapsulation was achieved
predominantly by capturing cisplatin during formation of liposomal vesicles.
The results
further indicate the physical state of cisplatin to be solid (aggregates) or
lipid bound since
the concentration of cisplatin is much higher than the solubility limit.
Results further
indicate that process does not require freezing the compositions, but that
cooling to
temperature higher than freezing can produce superior results. Results further
indicated
that an entrapment efficiency achieved by 3 cycles was similar to that
achieved by 6 cycles
of cooling and warming cycles, which indicated that 3 cycles of temperature
treatment was
sufficient to achieve highly preferred levels of entrapment.
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Results further indicate that the process can be scaled-up while increasing
process
efficiency in entrapping cisplatin. Thus, the invention further provides
processes that are
conducted to provide an amount adapted for total administration (in
appropriate smaller
volume increments) of about 200 or more mLs, about 400 or more mLs, or about
800 or
more mLs. All else being the same, it is believed that the larger production
volumes
generally achieve increased efficiency over smaller scale processes. While
such volume is
that appropriate for administration, it will be recognized that the volume can
be reduced for
storage.
Results further indicate that the lipid-complexed cisplatin made by this
method can
retain entrapped cisplatin with minimal leakage for over one year. This is a
further
demonstration of the uniqueness in the formulation, indicating that the
cisplatin is bound
within the liposome structure and not free to readily leak out.
Lipids
The lipids used in the compositions of the present invention can be synthetic,
semi-
synthetic or naturally-occurring lipids, and typically include phospholipids
and sterols. In
terms of phosholipids, they could include such lipids as egg
phosphatidylcholine (EPC),
egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg
phosphatidylserine
(EPS), phosphatidylethanolamine (EPE), and phosphatidic acid (EPA); the Soya
counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the
hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other phospholipids
made up
of ester linkages of fatty acids in the 2 and 3 of glycerol positions
containing chains of 12 to
26 carbon atoms and different head groups in the 1 position of glycerol that
include choline,
glycerol, inositol, serine, ethanolamine, as well as the corresponding
phosphatidic acids.
The chains on these fatty acids can be saturated or unsaturated, and the
phospholipid may
be made up of fatty acids of different chain lengths and different degrees of
unsaturation.
In particular, the compositions of the formulations can include DPPC, a major
constituent
of naturally-occurnng lung surfactant. Other examples include
dimyristoylphosphatidycholine (DMPC) and dimyristoylphosphatidylglycerol
(DMPG),
dipalmitoylphosphatidylglycerol (DPPG) distearoylphosphatidylcholine (DSPC)
and
distearoylphosphatidylglycerol (DSPG), dioleylphosphatidyl-ethanolarnine
(DOPE) and
mixed phospholipids like palmitoylstearoylphosphatidyl-choline (PSPC) and
palmitoylstearolphosphatidylglycerol (PSPG), and single acylated phospholipids
like mono-
oleoyl-phosphatidylethanolamine (MOPE).
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The sterols can include, cholesterol, esters of cholesterol including
cholesterol hemi-
succinate, salts of cholesterol including cholesterol hydrogen sulfate and
cholesterol sulfate,
ergosterol, esters of ergosterol including ergosterol hemi-succinate, salts of
ergosterol
including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol,
esters of lanosterol
including lanosterol hemi-succinate, salts of lanosterol including lanosterol
hydrogen
sulfate and lanosterol sulfate.
In a preferred embodiment of the invention the lipid composition contains 50
to 100
mol% DPPC and 0 to 50 mol% cholesterol. More preferably, the lipid complex
contains 50
to 65 mol% DPPC and 35 to 50 mol% cholesterol.
Inhalation Devices
The inhalation delivery device of the inhalation system can be a nebulizer, a
metered dose inhaler (MDI) or a dry powder inhaler (DPI). The device can
contain and be
used to deliver a single dose of the lipid compositions or the device can
contain and be used
to deliver mufti-doses of the lipid compositions of the present invention.
A nebulizer type inhalation delivery device can contain the compositions of
the
present invention as a solution, usually aqueous, or a suspension. In
generating the
nebulized spray of the compositions for inhalation, the nebulizer type
delivery device may
be driven ultrasonically, by compressed air, by other gases, electronically or
mechanically
(including, for example, a vibrating porous membrane). The ultrasonic
nebulizer device
usually works by imposing a rapidly oscillating waveform onto the liquid film
of the
formulation via an electrochemical vibrating surface. At a given amplitude the
waveform
becomes unstable, whereby it disintegrates the liquids film, and it produces
small droplets
of the formulation. The nebulizer device driven by air or other gases operates
on the basis
that a high pressure gas stream produces a local pressure drop that draws the
liquid
formulation into the stream of gases via capillary action. This fine liquid
stream is then
disintegrated by shear forces. The nebulizer may be portable and hand held in
design, and
may be equipped with a self contained electrical unit. The nebulizer device
can consist of a
nozzle that has two coincident outlet channels of defined aperture size
through which the
liquid formulation can be accelerated. This results in impaction of the two
streams and
atomization of the formulation. The nebulizer may use a mechanical actuator to
force the
liquid formulation through a multiorifice nozzle of defined aperture sizes) to
produce an
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aerosol of the formulation for inhalation. In the design of single dose
nebulizers, blister
packs containing single doses of the formulation may be employed.
In the present invention the nebulizer is employed to ensure the sizing of
aqueous
droplets containing the drug-lipid particles is optimal for positioning of the
particle within,
for example, the lungs. Typical droplet sizes for the nebulized lipid
composition are from
aboutl to about 5 microns.
For use with the nebulizer, the lipid composition preferably contains an
aqueous
component. Typically there is at least about 80% by weight and preferably, at
least about
90% by weight of the aqueous component in the lipid composition to be
administered with
a nebulizer. The aqueous component may include for example, saline. In
addition, the
aqueous component may include up to about 20% by weight of an aqueous
compatible
solvent such as ethanol.
Total administration time using a nebulizer will depend on the flow rate and
the
concentration of the cisplatin in the lipid composition. Variation of the
total administration
time is within the purview of those of ordinary skill in the art. Generally,
the flow rate of
the nebulizer will be at least about 0.15 mL/min, for example, a flow rate of
about 0.2
mL/min is typical. By way of example, administration of a dose of about 24
mg/m2 of
cisplatin using a lipid composition having a concentration of about 1 mg/mL of
cisplatin
would be about 4 hours (assuming a patient's body surface area is about 2 m2).
This
administration time may, for example, be split into two administration
sessions given over
the course of one or two days to complete one treatment cycle.
In alternative embodiments, a metered dose inhalator (MDI) can be employed as
the
inhalation delivery device of the inhalation system. This device is
pressurized (pMDI) and
its basic structure consists of a metering valve, an actuator and a container.
A propellant is
used to discharge the formulation from the device. The composition can consist
of particles
of a defined size suspended in the pressurized propellants) liquid, or the
composition can
be in a solution or suspension of pressurized liquid propellant(s). The
propellants used are
primarily atmospheric friendly hydroflourocarbons (HFCs) such as 134a and 227.
Traditional chloroflourocarbons like CFC-1 1, 12 and 114 are used only when
essential.
The device of the inhalation system may deliver a single dose via, e.g., a
blister pack, or it
may be multi dose in design. The pressurized metered dose inhalator of the
inhalation
system can be breath actuated to deliver an accurate dose of the lipid based
formulation. To
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insure accuracy of dosing, the delivery of the formulation may be programmed
via a
microprocessor to occur at a certain point in the inhalation cycle. The MDI
may be
portable and hand held.
In another alternative embodiment, a dry powder inhalator (DPI) can be used as
the
inhalation delivery device of the inhalation system. This device's basic
design consists of a
metering system, a powdered composition and a method to disperse the
composition.
Forces like rotation and vibration can be used to disperse the composition.
The metering
and dispersion systems may be mechanically or electrically driven and may be
microprocessor programmable. The device may be portable and hand held. The
inhalator
may be mufti or single dose in design and use such options as hard gelatin
capsules, and
blister packages for accurate unit doses. The composition can be dispersed
from the device
by passive inhalation; i.e., the patient's own inspiratory effort, or an
active dispersion
system may be employed. The dry powder of the composition can be sized via
processes
such as jet milling, spray dying and supercritical fluid manufacture.
Acceptable excipients
such as the sugars mannitol and maltose may be used in the preparation of the
powdered
formulations. These are particularly important in the preparation of freeze
dried liposomes
and lipid complexes. These sugars help in maintaining the liposome's physical
characteristics during freeze drying and minimizing their aggregation when
they are
administered by inhalation. The hydroxyl groups of the sugar may help the
vesicles
maintain their tertiary hydrated state and help minimize particle aggregation.
The inventive method is particularly well-suited for the treatment of lung
cancers,
particularly, bronchoalveolar carcinoma, or carcinomatosis with lymphangitic
spread. In
addition, both primary and metastatic lung cancers are excellent candidates
for the method
of the invention.
2 S Dog
The dosage of any composition of the present invention will vary depending on
the
symptoms, age and body weight of the patient, the nature and severity of the
disorder to be
treated or prevented, the route of administration, and the form of the
supplement. Any of
the subject formulations may be administered in a single dose or in divided
doses. Dosages
for the compounds of the present invention may be readily determined by
techniques
known to those of skill in the art or as taught herein. Also, the present
invention
contemplates mixtures of more than one subject compound, as well as other
therapeutic
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agents. Further, the present invention contemplates administration of the
therapeutic agent
that is contained in a subject coordination complex (or a related agent) in
conjunction with
the complex itself to increase the ratio of the therapeutic agent to the
coordination complex
formed upon release of the therapeutic agent,
In certain embodiments, the dosage of the subject compounds will generally be
in
the range of about 0.01 ng to about 10 g per kg body weight, specifically in
the range of
about 1 ng to about 0.1 g per kg, and more specifically in the range of about
100 ng to about
mg per kg.
An effective dose or amount, and any possible affects on the timing of
10 administration of the formulation, may need to be identified for any
particular compound of
the present invention. This may be accomplished by routine experiment as
described
herein, using one or more groups of animals (preferably at least 5 animals per
group), or in
human trials if appropriate. The effectiveness of any compound and method of
treatment or
prevention may be assessed by administering the supplement and assessing the
effect of the
administration by measuring one or more indices associated with the neoplasm
of interest,
and comparing the post-treatment values of these indices to the values of the
same indices
prior to treatment.
The precise time of administration and amount of any particular compound that
will
yield the most effective treatment in a given patient will depend upon the
activity,
pharmacokinetics, and bioavailability of a particular compound, physiological
condition of
the patient (including age, sex, disease type and stage, general physical
condition,
responsiveness to a given dosage and type of medication), route of
administration, and the
like. The guidelines presented herein may be used to optimize the treatment,
e.g.,
determining the optimum time and/or amount of administration, which will
require no more
than routine experimentation consisting of monitoring the subject and
adjusting the dosage
and/or timing.
While the subject is being treated, the health of the patient may be monitored
by
measuring one or more of the relevant indices at predetermined times during a
24-hour
period. Treatment, including supplement, amounts, times of administration and
formulation, may be optimized according to the results of such monitoring. The
patient
may be periodically reevaluated to determine the extent of improvement by
measuring the
same parameters, the first such reevaluation typically occurring at the end of
four weeks
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from the onset of therapy, and subsequent reevaluations occurring every four
to eight weeks
during therapy and then every three months thereafter. Therapy may continue
for several
months or even years, with a minimum of one month being a typical length of
therapy for
humans. Adjustments to the amounts) of agent administered and possibly to the
time of
administration may be made based on these reevaluations.
Treatment may be initiated with smaller dosages which are less than the
optimum
dose of the compound. Thereafter, the dosage may be increased by small
increments until
the optimum therapeutic effect is attained.
The combined use of several compounds of the present invention, or
alternatively
other chemotherapeutic agents, may reduce the required dosage for any
individual
component because the onset and duration of effect of the different components
may be
complimentary. In such combined therapy, the different active agents may be
delivered
together or separately, and simultaneously or at different times within the
day.
Toxicity and therapeutic efficacy of subject compounds may be determined by
standard pharmaceutical procedures in cell cultures or experimental animals,
e.g., for
determining the LDSO and the EDso. Compositions that exhibit large therapeutic
indices are
preferred. Although compounds that exhibit toxic side effects may be used,
care should be
taken to design a delivery system that targets the compounds to the desired
site in order to
reduce side effects.
The data obtained from the cell culture assays and animal studies may be used
in
formulating a range of dosage for use in humans. The dosage of any supplement,
or
alternatively of any components therein, lies preferably within a range of
circulating
concentrations that include the EDSO with little or no toxicity. The dosage
may vary within
this range depending upon the dosage form employed and the route of
administration
utilized. For agents of the present invention, the therapeutically effective
dose may be
estimated initially from cell culture assays. A dose may be formulated in
animal models to
achieve a circulating plasma concentration range that includes the ICSO (i.e.,
the
concentration of the test compound which achieves a half maximal inhibition of
symptoms)
as determined in cell culture. Such information may be used to more accurately
determine
useful doses in humans. Levels in plasma may be measured, for example, by high
performance liquid chromatography.
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Kits
This invention also provides kits for conveniently and effectively
implementing the
methods of this invention. Such kits comprise any of the compounds of the
present
invention or a combination thereof, and a means for facilitating compliance
with methods
of this invention. Such kits provide a convenient and effective means for
assuring that the
subject to be treated takes the appropriate active in the correct dosage in
the correct manner.
The compliance means of such kits includes any means which facilitates
administering the
actives according to a method of this invention. Such compliance means include
instructions, packaging, and dispensing means, and combinations thereof. Kit
components
may be packaged for either manual or partially or wholly automated practice of
the
foregoing methods. In other embodiments involving kits, this invention
contemplates a kit
including compositions of the present invention, and optionally instructions
for their use.
The following examples further illustrate the present invention, but of
course,
should not be construed as in any way limiting its scope.
Exen:plification
Example 1
70 mg of DPPC and 28 mg of cholesterol were dissolved in 1 mL of ethanol and
added to 10 mL of 4 mg/mL cisplatin in 0.9% saline solution. An aliquot (50%)
of the
sample was treated by 3 cycles of cooling to 4 °C and warming to 50
°C. The aliquot, in a
test tube, was cooled by refrigeration, and heated in a water bath. The
resulting
unentrapped cisplatin (free cisplatin) was washed by dialysis. The remainder
of the sample
was not treated by temperature cycles and directly washed by dialysis. Table 1
presents the
percentage entrapment of cisplatin with and without cooling an warming cycles.
Table 1. Cisplatin percentage entrapment.
Final Concentration
of Entrapment
cis latin, ~g/ml
Lipid-complexed
cisplatin
without cooling 56 1.4
and
warming c cles
Lipid-complexed
cisplatin
after cooling and 360 9.0
warming
cycles
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Example 2
1.0 g of DPPC and 0.4 g of cholesterol were dissolved in 6 mL of ethanol. 60
mg of
cisplatin was dissolved in 10 mL of 0.9% saline solution at 65 °C. 1 mL
of the resultant
lipid mixture solution was added to 10 mL of the resultant cisplatin solution.
The
lipid/cisplatin suspension was cooled to approximately 4 °C and held at
that temperature for
20 minutes and warmed to 50 °C and held at that temperature for 20
minutes. Ethanol was
removed by bubbling NZ gas into the suspension during the warming period. The
cooling
and warming steps were repeated 5 further times. The concentration of total
cisplatin was
5.8 mg/mL with 91.6% entrapped cisplatin and drug : lipid ratio (by weight) of
1 : 26.
Example 3
A liposomal formulation was prepared using phosphatidylcholine (PC) and
cholesterol (in a 57:43 mol ratio). 0.55 mmoles of PC and 0.41 mmoles of
cholesterol were
dissolved in 2 mL ethanol and added to 20 mL of 4 mg/mL cisplatin solution. An
aliquot
(50%) of each sample was treated by 3 cycles of cooling and warming and then
washed by
dialysis. Another part of each sample was directly washed by dialysis.
Entrapment was
estimated from the ratio of final concentration and initial concentration.
Table 2. Entrapment and drug to lipid ratios for cisplatin with various
phophatidylcholines.
No Cooling Cooling Warming
and and
Warmin
PC Final % Drug:LipidFinal % Drug:Lipid
[Cisplatin]Entrapment(by weight)[Cisplatin]En~.apment(by weight)
(mg/mL) (mg/mL)
DOPC 0.16 4.0 1:142 0.21 5.3 1:108
EggPC 0.09 2.3 1:247 0.12 3.0 1:185
DMPC 0.15 3.8 1:123 0.24 6.0 1:77
DPPC 0.17 4.3 1:115 0.85 21.3 1:23
HSPC 0.11 2.8 1:202 0.23 5.8 1:97
DSPC 0.10 2.5 1:184 0.58 14.5 1:32
Example 4
A lipid formulation (DPPC:cholesterol in a ratio of 5:2 w/w) was dissolved in
ethanol and added to a cisplatin solution. Part of the formulation was treated
by cycles of
cooling to 4 °C and warming to SS °C cycles while part was not
treated thus. The
lipid/cisplatin suspension was then washed by dialysis.
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Table 3. Concentration of cisplatin with and without cooling and warming
cycles.
Starting Concentration Total concentration
of
concentration Cooling & warming
of lipids of Cisplatin
Cisplatin (m~mL) cycles (mg/mL)
solution
(mg/mL)
0.2 1.4 No Not Detectable
0.2 1.4 Yes Not Detectable
4.0 28 No 0.22
4.0 28 Yes 0.46
Example 5
Dosin , Schedule
Patients are dosed with a jet nebulizer (Pari LC Star) which is filled with up
to about
7 mL of the lipid composition (containing about 1 mg/mL of cisplatin) which is
formulated
with saline. The flow rate of the lipid composition from the nebulizer is
about 0.2 mL/min.
At this rate, for example, administration of about 4 mL of the lipid
composition takes about
20 minutes. Table 4 indicates the dosing schedule.
Table 4. Dosing schedule.
Frequency of Treatment
Dose / Treatment # of Treatment
atientCycle Cycles Cycles
(mg/m2) (week(s )
1 1.5 3 6 (i.e., 18
weeks)
2 3.0 3 6
3 6.0 3 6
4 12.0 3 6
5 24.0 3 6
6 48.0 3 6
7 24.0 2 6 (i.e., 12
weeks)
8 36.0 2 6
9 48.0 2 6
10 24.0 1 12 (i.e.,
3 months)
Patient numbers 1, 3, and 9, of the ongoing study have shown stabilization
(i.e., no
further tumor growth or tumor growth of less than 20%).
Incorporatiorr by Reference
All of the patents and publications cited herein are hereby incorporated by
reference.
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Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following claims.
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